This research project is designed to provide an animal model and to study the biochemical mechanisms involved in the development of tolerance to and physical dependence on barbiturates. With the recently developed pentobarbital pellet implantation procedure in this laboratory, we have been able to induce a much greater degree of tolerance to the hypnotic effects of pentobarbital in a shorter period of time than that produced by the conventional parenteral adminstration technique. The research plan proposes (1) to differentiate between physiological disposition of tolerance and CNS adaptive tolerance to pentobarbital; (2) to quantify physical dependence after barbiturate withdrawal; (3) to study the relationship between neurotransmitters and the acute effects of pento- barbital; and (4) to assess the contributory role of the putative neurotransmitters in pentobarbital tolerance and dependence mechanisms in the CNS. Other barbiturates such as barbital and phenobarbital will be studied with the same technique in order to see the generalization of mechanisms on barbiturate tolerance and dependence. Cross-tolerance and dependence with non-barbiturate type hypnotics lead us to a better understanding of the mechanisms concerned with barbiturate tolerance and physical dependence and thus provide a more rational basis for the treatment of barbiturate abuse in human.